Treatment of HER2 positive cancers

Abstract

In one aspect, the present invention provides a method for treating or ameliorating the effects of a HER2 positive cancer in a subject. In some embodiments, the method comprises administering a combination therapy comprising an anti-HER2 antibody and tucatinib. In some embodiments, the method further comprises administering a chemotherapeutic agent (e.g., an antimetabolite) to the subject. Pharmaceutical compositions and kits are also provided herein.

What is claimed is: 
     
       1. A method for treating a HER2-positive cancer in a subject, the method comprising:
 administering a combination therapy comprising an anti-HER2 antibody and tucatinib, thereby treating the HER2-positive cancer, 
 wherein the HER2-positive cancer is selected from the group consisting of: colorectal cancer, gastric cancer, lung cancer, biliary cancers, and esophageal cancer. 
 
     
     
       2. The method of  claim 1 , wherein the combination therapy further comprises a chemotherapeutic agent. 
     
     
       3. The method of  claim 2 , wherein the chemotherapeutic agent is an antimetabolite. 
     
     
       4. The method of  claim 3 , wherein the antimetabolite is capecitabine. 
     
     
       5. The method of  claim 1 , wherein the HER2-positive cancer is biliary cancer. 
     
     
       6. The method of  claim 1 , wherein the HER2-positive cancer is an unresectable locally advanced cancer or a metastatic cancer. 
     
     
       7. The method of  claim 1 , wherein the HER2-positive cancer is lung cancer. 
     
     
       8. The method of  claim 1 , wherein the subject had prior treatment with trastuzumab, pertuzumab, or T-DM1. 
     
     
       9. The method of  claim 1 , wherein the anti-HER2 antibody is a member selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab emtansine, margetuximab, and a combination thereof. 
     
     
       10. The method of  claim 1 , wherein the anti-HER2 antibody is trastuzumab. 
     
     
       11. The method of  claim 1 , wherein the HER2-positive cancer comprises a cell that has a wild-type KRAS exon 2 genotype, a wild-type NRAS genotype, or a wild-type BRAF genotype. 
     
     
       12. The method of  claim 1 , wherein the subject has a HER2-positive cancer which is relapsed or refractory to a standard of care. 
     
     
       13. The method of  claim 1 , wherein treating the subject results in a tumor growth inhibition (TGI) index of at least about 85%. 
     
     
       14. The method of  claim 1 , wherein the combination of the anti-HER2 antibody and tucatinib is synergistic. 
     
     
       15. The method of  claim 14 , wherein treating the subject results in a TGI index that is greater than the TGI index observed when using an anti-HER2 antibody or tucatinib alone. 
     
     
       16. The method of  claim 1 , wherein a dose of tucatinib is about 300 mg administered twice per day. 
     
     
       17. The method of  claim 1 , wherein a dose of the anti-HER2 antibody is about 6 mg to 8 mg per kg of the subject's body weight administered once every three weeks. 
     
     
       18. The method of  claim 1 , wherein a dose of the anti-HER2 antibody is about 600 mg administered once every three weeks. 
     
     
       19. The method of  claim 1 , wherein the tucatinib or the anti-HER2 antibody is administered orally. 
     
     
       20. The method of  claim 3 , wherein the antimetabolite is administered orally. 
     
     
       21. The method of  claim 20 , wherein a dose of the antimetabolite is about 1,000 mg per m 2  of the subject's body surface area administered twice per day. 
     
     
       22. The method of  claim 1 , wherein the anti-HER2 antibody is administered intravenously or subcutaneously. 
     
     
       23. The method of  claim 1 , wherein one or more therapeutic effects in the subject is improved after administration of the combination therapy relative to a baseline. 
     
     
       24. The method of  claim 23 , wherein the one or more therapeutic effects is selected from the group consisting of: size of a tumor derived from the HER2-positive cancer, objective response rate, duration of response, time to response, progression free survival, and overall survival. 
     
     
       25. The method of  claim 1 , wherein the subject has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events. 
     
     
       26. The method of  claim 1 , wherein the subject is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events. 
     
     
       27. The method of  claim 1 , wherein the subject is a human. 
     
     
       28. A method for treating a HER2-positive cancer in a subject comprising:
 (a) administering to the subject a combination therapy comprising an anti-HER2 antibody and tucatinib at an initial dosage level, wherein the subject exhibits an adverse event after administration of the combination therapy at the initial dosage level, and 
 (b) administering to the subject the combination therapy at a reduced dosage level, 
 wherein the HER2-positive cancer is selected from the group consisting of: colorectal cancer, gastric cancer, lung cancer, biliary cancers, and esophageal cancer. 
 
     
     
       29. The method of  claim 28 , wherein the combination therapy further comprises a chemotherapeutic agent. 
     
     
       30. The method of  claim 29 , wherein the chemotherapeutic agent is an antimetabolite. 
     
     
       31. The method of  claim 30 , wherein the antimetabolite is capecitabine. 
     
     
       32. The method of  claim 28 , wherein the one or more adverse events is a grade 2 adverse event, a grade 3 adverse event, or a greater adverse event. 
     
     
       33. The method of  claim 28 , wherein the adverse event is hepatotoxicity, left ventricular dysfunction, or prolongation of the QTc interval. 
     
     
       34. The method of  claim 28 , wherein the HER2-positive cancer is an unresectable locally advanced cancer or a metastatic cancer. 
     
     
       35. The method of  claim 28 , wherein the HER2-positive cancer is lung cancer. 
     
     
       36. The method of  claim 28 , wherein the subject had prior treatment with trastuzumab, pertuzumab, or T-DM1. 
     
     
       37. The method of  claim 28 , wherein the initial dosage level of tucatinib is about 300 mg administered twice daily. 
     
     
       38. The method of  claim 28 , wherein the reduced dosage level of tucatinib is about 250 mg administered twice daily. 
     
     
       39. The method of  claim 28 , wherein the reduced dosage level of tucatinib is about 200 mg administered twice daily. 
     
     
       40. The method of  claim 28 , wherein the reduced dosage level of tucatinib is about 150 mg administered twice daily. 
     
     
       41. The method of  claim 28 , wherein the HER2-positive cancer is biliary cancer. 
     
     
       42. The method of  claim 5 , wherein the biliary cancer is cholangiocarcinoma. 
     
     
       43. The method of  claim 7 , wherein the lung cancer is non-small cell lung cancer. 
     
     
       44. The method of  claim 1 , wherein the HER2-positive cancer is colorectal cancer. 
     
     
       45. The method of  claim 1 , wherein the HER2-positive cancer is gastric cancer. 
     
     
       46. The method of  claim 1 , wherein the HER2-positive cancer is esophageal cancer. 
     
     
       47. The method of  claim 28 , wherein the anti-HER2 antibody is a member selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab emtansine, margetuximab, and a combination thereof. 
     
     
       48. The method of  claim 28 , wherein the anti-HER2 antibody is trastuzumab. 
     
     
       49. The method of  claim 35 , wherein the lung cancer is non-small cell lung cancer. 
     
     
       50. The method of  claim 41 , wherein the biliary cancer is cholangiocarcinoma. 
     
     
       51. The method of  claim 28 , wherein the HER2-positive cancer is colorectal cancer. 
     
     
       52. The method of  claim 28 , wherein the HER2-positive cancer is gastric cancer. 
     
     
       53. The method of  claim 28 , wherein the HER2-positive cancer is esophageal cancer.